PET imaging of beta-secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [18F]PF-06684511

Ryosuke Arakawa; Akihiro Takano; Per Stenkrona; Vladimir Stepanov; Sangram Nag; Mahabuba Jahan; Per Grybäck; Martin Bolin; Laigao Chen; Lei Zhang; Ping He; Anabella Villalobos; Timothy J McCarthy; Christer Halldin; Andrea Varrone

doi:10.1007/s00259-020-04739-5

PET imaging of beta-secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [¹⁸F]PF-06684511

Eur J Nucl Med Mol Imaging. 2020 Sep;47(10):2429-2439. doi: 10.1007/s00259-020-04739-5. Epub 2020 Mar 6.

Authors

Affiliations

¹ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden. ryosuke.arakawa@ki.se.
² Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
³ Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁴ Worldwide Research & Development, Pfizer Inc., Cambridge, MA, USA.

Abstract

Purpose: Beta-secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer's disease. [¹⁸F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [¹⁸F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [¹⁸F]PF-06684511 in healthy volunteers.

Methods: Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (V_T) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of V_T were calculated as reliability measures.

Results: In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 μSv/MBq). The calculated ED was 24.7 ± 0.8 μSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. V_T (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of V_T (2TCM) were 16.5% (12.4-20.5%) and 0.496 (0.291-0.644).

Conclusion: The ED of [¹⁸F]PF-06684511 was similar to other ¹⁸F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of V_T was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [¹⁸F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain.

Trial registration: EudraCT 2016-001110-19 (registered 2016-08-08).

Keywords: Beta-secretase 1 (BACE1); Dosimetry; Human brain; Positron emission tomography (PET); Test-retest repeatability.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Amyloid Precursor Protein Secretases*
Aspartic Acid Endopeptidases
Brain / diagnostic imaging
Humans
Male
Positron Emission Tomography Computed Tomography*
Positron-Emission Tomography
Radiometry
Radiopharmaceuticals
Reproducibility of Results
Tissue Distribution
Tomography, X-Ray Computed

Substances

Radiopharmaceuticals
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases